Abstract
Fear and pain are two frequently co-occurring states that mammals need to orchestrate to ensure survival. Nevertheless, how the brain dynamically prioritizes between them remains poorly understood. Here, we demonstrate that innate fear suppresses both acute and chronic pain, whereas pain does not reciprocally modulate fear responses in male mice. Using fiber photometry, virus tracing, and electrophysiological approaches, we show that exposure to a fear-inducing odor activates GABAergic neurons in the anterior piriform cortex (APC), which subsequently attenuates pain-associated hyperactivity in the downstream mediodorsal thalamus (MD). Crucially, inhibiting either APCGABA neurons or the APCGABA-MD circuit enhances pain sensitivity and abolishes fear-induced analgesia. Conversely, activation of APCGABA neurons or the APCGABA-MD circuit induces freezing responses and relieves pain, mimicking fear-induced analgesia. These findings unveil a corticothalamic circuit that bidirectionally regulates pain processing and underlies fear-provoked analgesia, offering potential therapeutic avenues for pain management.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (grants 32271048, 32571336, 32070999 to Y.Z., grant 82471311 to W.H., and grant 823B2022 to X.Y.W), the Leading Medicine and Advanced Technologies of IHM (grant 2025IHM01100 to Y.Z.), and Anhui Provincial Natural Science Foundation (grant 2008085J16 to Y.Z.).
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W.B.J., X.Y.W., and X.X.X. designed the studies and conducted most of experiments and data analysis. L.T., Y.X.L, and X.L.L. were involved in the revision. X.Q.L. managed the mouse colonies used in this study. Y.Z., W.B.J., and X.Y.W. wrote the first draft. W.H. and Y.Z. were involved in the overall design of the project and editing of the final manuscript.
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Jia, WB., Wang, XY., Xia, XX. et al. A corticothalamic circuit modulates pain sensitivity and mediates innate fear-induced analgesia in male mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70580-3
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DOI: https://doi.org/10.1038/s41467-026-70580-3
